Liposomal Protection of Adriamycin-induced Cardiotoxicity in Mice¹

The pharmacological and therapeutic effects of Adriamycin entrapped in positively charged and negatively charged liposomes were compared with those of free Adriamycin in mice. Liposomes were composed of phosphatidylcholine and cholesterol mixed with stearyl amine (positive charge) or phosphatidylserine (negative charge). Positive liposomes with entrapped Adriamycin effectively retarded the in vivo uptake of drug in cardiac tissue when compared to free drug or drug entrapped in negative liposomes. At 4 mg/kg i.v., the peak drug concentration in heart occurred in 30 min following administration of free Adriamycin or Adriamycin entrapped in negative liposomes, compared to 5 min with Adriamycin entrapped in positive liposomes. The maximum drug concentration achieved with positive liposomes in cardiac tissue was approximately one-half that of free drug or drug entrapped in negative liposomes. In addition, the cardiac concentration × time values for Adriamycin administered in positive liposomes were considerably less than that of free drug or negative liposomes for the 24-hr period of observation. The liposomal Adriamycin was preferentially concentrated in liver, spleen, and lungs. Electron microscopic studies demonstrated that the myocytes and myofibrillar structure of cardiac muscle were markedly well preserved with Adriamycin in positive liposomes, in contrast to the two other delivery forms. The antitumor activity of the drug against murine ascitic P388 leukemia and Lewis lung carcinoma demonstrated an identical effect when administered as free drug or entrapped in positive liposomes. The specific positively charged liposome developed in these studies selectively reduces the acute cardiotoxicity of Adriamycin without loss of antitumor activity.